Asthma is a common chronic inflammatory disease of the lungs characterized by episodic respiratory symptoms. Until recently, asthma was considered an essentially reversible disorder, but chronic airway inflammation in asthma is now thought to lead to structural alterations and irreversibility. Evidence suggests that individuals with more severe asthma have increased airway remodeling. In addition, several studies show that individuals with asthma suffer an accelerated decline in lung function. Whether subjects with more severe asthma suffer a faster rate of decline in lung function compared with other individuals with asthma is still controversial. Furthermore, despite the numerous genetic studies on asthma, the role that individual genetic susceptibility plays in airway response to chronic inflammation in asthma is unknown. Polymorphisms in genes have been associated with accelerated decline in lung function in other diseases; however there are surprisingly few long-term studies on the natural course of lung function in asthma and genetic predisposition to lung function decline. The proposed research project will focus on estimating the association of asthma and asthma severity with rate of lung function decline (Specific Aim 1); as well as identifying polymorphisms in candidate genes associated with asthma severity and rate of lung function decline (Specific Aim 2). We will employ a cohort design, building on an ongoing study in Barbados. The Barbados Asthma Genetics Study, initiated in 1993 represents one of the largest asthma study populations of African descent and provides a unique opportunity to study individuals with asthma for whom rich phenotypic and baseline lung function data are available. Our long range goal is to identify genetic polymorphisms that mark high risk individuals for early intervention to decrease asthma morbidity. Nadia Hansel, MD MPH is committed to a career in clinical investigation, with a focus on the genetics of asthma severity. During the proposed study period, career development activities will include one-on-one mentoring, didactic work, relevant clinical work, development and conduct of a research project, presentation of research findings, and learning to teach research skills. This body of mentored patient-oriented research will provide Dr. Hansel new knowledge, skills and collaborative relationships necessary to successfully apply for funding as an independent investigator during the fourth year of this award.